Curcumin is a naturally occurring compound of the curcuminoid family, isolated originally from the plant Curcuma longa. The rhizome of this plant, specifically, is used to create the spice known as turmeric, and is a major component of the daily diet in many Asian countries. Even before the modern characterization of curcumin's molecular structure and functionality, it has long been used in traditional eastern medicines.
With its natural medicinal history in mind, curcumin has been studied extensively over the past few decades in a wide variety of systems, and has been found to exhibit significant pleiotropic effects. These effects may be attributed to the chemistry of curcumin, consisting of two polyphenolic rings joined by a conjugated, flexible linker region with a β-diketone moiety at its center. The β-diketone moiety is capable of undergoing keto-enol tautomerization, though the enol form is more stable in both the solid phase and in solution (Gupta, S. C. et al. 2011) and is the dominant species at physiological pH (Gupta, S. C. et al. 2011; Zhang, Y. et al. 2012). The biological activities of curcumin are wide ranging: beyond having intrinsic antioxidant properties, it has been found to bind a wide spectrum of cellular constituents in vitro and in vivo, including inflammatory molecules, protein kinases, carrier proteins, cell survival proteins, structural proteins, the prion protein, antioxidant response elements, metal ions, and more (Gupta, S. C. et al. 2011). In addition, curcumin shows virtually no toxicity in humans (Gupta, S. C. et al. 2011; Ammon, H. P. T. et al. 1991).
While curcumin has been shown to have multiple beneficial effects, its poor oral absorption and lack of solubility in physiological fluid has all but precluded its use as a medicinal substance. Therefore, novel chemically-modified curcumins with enhanced pharmacokinetic and pharmacodynamic properties are needed.
Melanocytes are specialized cells which originate from the neural crest and have a key role in synthesis of melanin, a biopolymeric pigment inside organelles called melanosomes which are secreted and transferred to keratinocytes in the epidermis. Melanosomes progress through four stages of maturation [Cichorek, M. et al. 2013]. Melanocytes are present in basal layer of the epidermis and connect to neighboring keratinocytes via dendrites and one melanocyte contacts up to 30-40 keratinocytes to transfer melanin [Fitzpatrick, T. B. et al. 1963]. The process involves synthesis, packaging, transfer and uptake of melanin by keratinocytes [Ando, H. et al. 2012] which is ultimately responsible for skin coloration. Melanin provides UV photo-protection and scavenges free radicals; however, an excessive production of melanin in the skin can lead to hyperpigmentation, also called as hypermelanosis, and is associated with medical skin disorders such as melasma, post-inflammatory hyperpigmentation (PIH) and lentigosenilis (LS). It also causes significant psychosocial burden.
Tyrosinase (EC 1.14.18.1) is the rate-limiting enzyme in melanin synthesis pathway which catalyzes the conversion of L-tyrosine to L-Dopa and subsequent conversion to L-Dopaquinone. Tyrosinase is a membrane-bound glycoprotein consisting of two copper atoms in its active site [Chang, T. S. 2009]. Hence, compounds which can chelate copper can inhibit tyrosinase activity. The most popular commercial skin whitening agents, such as kojic acid, hydroquinone and arbutin (glycosylated hydroquinone) are tyrosinase inhibitors. However, all these exhibit serious side-effects; kojic acid causes pigmented contact dermatitis [García-Gavín, J. et al. 2010], hydroquinone is carcinogenic [Kooyers, T. et al. 2006] and arbutin has potent genotoxicity [Cheng, S. L. et al. 2007]. These limitations have prompted an interest in identifying novel and natural plant-derived compounds without adverse effects, for treatment of hyperpigmentation both in cosmetic and clinical settings.